Origins of Eukaryotic Sexual Reproduction

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Origins of Eukaryotic Sexual Reproduction
Ursula Goodenough1 and Joseph Heitman2

1
Department of Biology, Washington University, St. Louis, Missouri 63130
2
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham,
North Carolina 27710
Correspondence: ursula@biology2.wustl.edu; heitm001@duke.edu
Sexual reproduction is a nearly universal feature of eukaryotic organisms. Given its ubiquity
and shared core features, sex is thought to have arisen once in the last common ancestor
to all eukaryotes. Using the perspectives of molecular genetics and cell biology, we con-
sider documented and hypothetical scenarios for the instantiation and evolution of meio-
sis, fertilization, sex determination, uniparental inheritance of organelle genomes, and
speciation.
he transition from prokaryote to protoeu- tion of ploidy via cell – cell fusion and meiosis;
T karyote to the last eukaryotic common an-
cestor (LECA) entailed conservation, modifica-
(2) mating-type regulation of cell – cell fusion
via differentiation of complementary haploid
tion, and reconfiguration of preexisting genetic gametes (isogametic and then anisogametic),
circuits via mutation, horizontal gene transfer a prelude to species-isolation mechanisms; (3)
(HGT), endosymbiosis, and selection, as de- mating-type-regulated coupling of the dip-
tailed in previous articles of this collection. Dur- loid/meiotic state to the formation of adap-
ing the course of this evolutionary trajectory, the tive diploid resting spores; and (4) mating-
LECA became sexual, reassorting and recombin- type-regulated transmission of organelle ge-
ing chromosomes in a process that entails regu- nomes. Our working assumption is that
lated fusions of haploid gametes and diploid ! the protoeukaryote ! LECA era featured nu-
haploid reductions via meiosis. That the LECA merous sexual experiments, most of which
was sexual is no longer a matter of speculation/ failed but some of which were incorporat-
debate as evidence of sex, and of genes exclusively ed, integrated, and modified. Therefore, this
involved in meiosis, has been found in all of the list is not intended to suggest a sequence of
major eukaryotic radiations (Brawley and John- events; rather, the four innovations most like-
son 1992; Ramesh et al. 2005; Kobiyama et al. ly coevolved in a parallel and disjointed fash-
2007; Malik et al. 2008; Phadke and Zufall ion.
2009; Fritz-Laylin et al. 2010; Lahr et al. 2011; Once these core sexual-cycle themes were in
Peacock et al. 2011; Vanstechelman et al. 2013). place, the evolution of eukaryotic sex has fea-
We propose that the transition to a sexual tured countless prezygotic and postzygotic var-
LECA entailed four innovations: (1) alterna- iations, the outcome being the segregation of
Editors: Patrick J. Keeling and Eugene V. Koonin

Additional Perspectives on The Origin and Evolution of Eukaryotes available at www.cshperspectives.org
Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a016154
Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016154
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U. Goodenough and J. Heitman
panmictic populations into distinct species cell– cell fusion entailed the engulfment of one
with distinctive adaptations. protoeukaryote by another, with the internal-
For additional reviews on the evolution of ized cell membrane then either digested or fused
sex, the interested reader is referred to Goode- with the host cell membrane from within.
nough (1985), Dacks and Roger (1999), Schurko Increases in ploidy confer indubitable ben-
et al. (2009), Wilkins and Holliday (2009), Gross efits: The resultant redundancy allows novel se-
and Bhattacharya (2010), Lee et al. (2010), quences/functions to arise in duplicate genes
Perrin (2012), and Calo et al. (2013). without compromising existing pathways, and
recessive nonadaptive alleles, masked but car-
ried through time, may prove to be adaptive
ALTERNATION OF PLOIDY VIA CELL – CELL in future contexts. Another potential benefit
FUSION AND MEIOSIS of cell– cell fusion is hybrid fitness: If, as seems
likely, there existed a variety of fledgling proto-
The Benefits and Challenges of Increased
eukaryotes in the population that eventually
Genome Size and Ploidy
gave rise to the LECA, then their fusion would
Modern bacteria, and presumably their fore- be expected to have yielded more gene-rich and
bears, are adept at taking up DNA from outside occasionally more successful lineages.
sources (Narra and Ochman 2006). The proto- Increases in genome size/ploidy are expect-
eukaryote, probably at some early stage in its ed to eventually become deleterious, however,
evolution, was also phagocytic, at least occasion- one challenge being to organize a successful mi-
ally, salient evidence being its engulfment of a tosis, another to regulate appropriate levels of
proteobacterium that was then domesticated as gene expression. Hence, there would presum-
the mitochondrion. Phagocytosis in modern ably have been positive selection for the acqui-
cells is a complex process involving hundreds sition of mechanisms to maintain copy number
of proteins (Boulais et al. 2010), but early ver- at a manageable size.
sions can be assumed to have been less sophisti- In recent studies, a broad panel of Saccha-
cated, and cell membranes capable of engaging romyces cerevisiae and Saccharomyces paradoxus
in phagocytosis would presumably also have strains were tested as haploids and diploids un-
been capable of engaging in cell – cell fusions, der diverse conditions (Zorgo et al. 2013). For
as is the case for wall-less mutants of modern about half of the conditions tested in which
bacteria (Errington 2013). It has been suggested there was a difference (such as growth with ra-
(Rose 1983; Hickey 1982, 1993) that early cell – pamycin or phleomycin), haploids were more
cell fusions might have been promoted by “self- fit, whereas for the other half (such as exposure
ish” transposons and plasmids that incur repli- to heat or ethanol), diploids had increased fit-
cative advantage in novel genomic contexts; pos- ness. Which ploidy state was less fit was highly
sible evidence for this hypothesis (Keeling and correlated between the two species that are di-
Roger 1995) is the use of the HO endonuclease verged over several million years. These findings
or a transposase (Barsoum et al. 2010; Rusche suggest that the ability to interconvert from
and Rine 2010), conscripted from ancestral haploid to diploid and back again might be
transposable elements, to effect mating-type beneficial when conditions shift from those fa-
switching in several yeasts. voring the haploid state to those favoring the
Cell– cell fusion generates an increase in diploid state (or vice versa). Thus, sexual repro-
chromosome number, and although the large duction might confer benefits for organisms
size of modern eukaryotic genomes could also just by enabling these rapid ploidy transitions,
have been the consequence of endomitosis, it independent of any role in shuffling genetic
seems likely that cell– cell fusions contributed composition by recombination, with endorepli-
to genome expansion during protoeukaryote cation being another avenue. That said, the abil-
evolution. An alternative possibility, leading to ity to toggle from haploid to diploid and back
the same outcome, is that the earliest versions of again is dependent on a mechanism for ploidy
2 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016154

reduction, which, in modern eukaryotes, entails Parasexuality in Candida albicans

meiotic or parasexual processes.
We also know about an unusual parasexual cycle
that is extant in the most common human fun-
PARASEXUALITY
gal pathogen, Candida albicans (Bennett et al.
In the following sections, in which we consider 2005; Sherwood and Bennett 2009; Berman
the origins and evolution of parasexual and 2012). In this species, mating occurs between
meiosis-based sexual cycles, we use as examples diploids when the mating-type locus is homo-
modern organisms whose mating-type-based zygous (a/a and a/a) and the cells switch to a
sexual differentiation is already established. In specialized mating cell type called opaque (Mil-
subsequent sections we will consider how sexual ler and Johnson 2002). Cell – cell fusion then
differentiation itself might have originated and generates tetraploid cells, and adverse media
evolved. conditions stimulate random chromosome
loss to return to a diploid, or near diploid, state
via a parasexual process (Bennett and Johnson
Parasexuality in Aspergillus
2003; Forche et al. 2008). Given that Candida is
As one must walk before one can run, the fusion embedded among sexual fungi (Butler et al.
of cells may have led to early parasexual cycles 2009), this is presumably an example of a de-
from which true meiotic sexual cycles evolved at rived parasexual state, but one can envision
a later time. We know a great deal about extant analogous earlier versions of genetic exchange
parasexual cycles from the classic work of Pon- involving cell–cell fusion followed by parasexu-
tecorvo on the filamentous fungus Aspergillus al ploidy change from which true sexual cycles
nidulans in the 1950s, and these can provide evolved via the invention of meiosis. In this view,
insight into both possible ancestral states as the evolution of meiosis would have been a late
well as more recent derived states given that step in the evolution of sexual cycles.
parasexuality, like asexuality, is likely both an In the C. albicans parasexual cycle, a low level
ancestral and a derived state (Pontecorvo 1956). of chromosomal recombination is detected in
Aspergillus has a bona fide homothallic (self- addition to chromosome loss and assortment,
ing) sexual cycle, but also undergoes a parasex- and these recombination events require the
ual cycle under laboratory conditions: Diploids function of the C. albicans Spo11 ortholog
are generated from haploid progenitors by hy- (Forche et al. 2008), a central player in meiosis.
phal fusion and the resulting diploid then loses One interpretation is that the functions of Spo11
chromosomes randomly to return to the hap- have been reconfigured to play a mitotic, para-
loid state. Recent studies have shown that this sexual role. Alternatively, the parasexual cycle of
parasexual cycle provides access to a sheltered C. albicans could involve some aspects of meio-
diploid state that can serve as a capacitor for sis (such as Spo11-dependent chiasmata), but
evolution (Schoustra et al. 2007): More rapidly given the high rate of aneuploidy (e.g., 2N þ
growing variants readily arise from homozygous 1, 2N þ 2) that is generated, it does not produce
diploids, but not from the corresponding hap- accurate outcomes, and might be considered
loid “parent,” and they are then reduced to a something akin to a “parameiosis” (Becker and
haploid state. The faster growing variants prove De Castro-Prado 2004; Wilkins and Holliday
to harbor multiple recessive alleles, reciprocally 2009; Heitman 2010). Studies on whether other
epistatic, that together are beneficial but indi- meiotic orthologs are involved may further illu-
vidually are deleterious, and thus they can only minate this interesting example of what could
accumulate in the diploid and then be released represent a derived state similar to an ancestral
during parasexual genome reduction. These parasexual-sexual transitional intermediate.
studies illustrate the capacity of haploid-dip- Numerous studies have identified genes ex-
loid-haploid parasexual cycles to generate geno- pressed exclusively in cells undergoing meiosis,
typic and phenotypic diversity de novo. generating an inventory of “meiosis-specific
Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016154 3

genes” (Schurko and Logsdon 2008). The C. genome and also reveals recessive alleles in hap-
albicans genome was reported to be missing loid progeny of a heterozygous diploid progen-
members of this list, which would be consistent itor. The return to the diploid state may have
with its parasexual cycle (Tzung et al. 2001). To initially entailed endoreplication, with cell–
explore what might be required in related spe- cell fusion mechanisms evolving later. Advan-
cies, a series of Candida species that are para- tages of meiosis compared with parasexual
sexual, asexual, and fully sexual was sequenced mechanisms are fidelity and more extensive in-
(Butler et al. 2009). Quite remarkably, two sex- trachromosomal recombination, at least for the
ual species were found to be missing key mat- forms of meiosis that are extant today.
ing-type locus genes and yet remain sexually In either view, the enzymes and machinery
fertile. Moreover, the sexual species were miss- for meiosis presumably evolved from a core set
ing the same key meiotic genes as C. albicans, as of DNA-manipulating enzymes brought in and
well as two dozen others! That the unusual sex- modified as needed from prokaryotic forebears,
ual species Candida lusitaniae truly undergoes including both bacterial and archaeal lineages
meiosis was documented experimentally, and (Marcon and Moens 2005). We see this evolu-
thus the gene repertoire to complete meiosis is tionary history quite clearly in the case of
apparently more plastic than thought (Reedy Spo11 (Klapholz et al. 1985; Wagstaff et al.
et al. 2009). Quite interestingly, this sexual spe- 1985), which introduces the DNA double-
cies produces about two-thirds euploid proge- strand breaks (DSBs) that provoke meiotic re-
ny, whereas one-third is either aneuploid or combination (Cao et al. 1990; Keeney et al. 1997;
diploid, possibly because they fail to execute Schurko and Logsdon 2008). Spo11 is derived
meiosis properly in the absence of important from an ancestral archaeal topoisomerase VI ho-
components. Thus, like a V8 engine missing molog that became included in the protoeukar-
one spark plug, or a dog with three legs, the yote genome and was then adapted for meiosis
engine or animal can run but it is not pretty. (Bergerat et al. 1997). In essence, Spo11 is a
Sex in nature may be messier than when studied topoisomerase that lost the ability to re-ligate
in the laboratory with optimized S. cerevisiae DNA. That Spo11 was present in the LECA can
strains, such as SK1 (which sporulates and ger- be inferred by its presence in all of the major
minates at higher frequency than many other eukaryotic lineages studied thus far, with the
isolates) (Ben-Ari et al. 2006), and meiotic in- notable exception of Dictyostelium discoidium
fidelity may in fact function as a further source and closely related slime molds that have appar-
of diversity generated by sexual reproduction. ently lost Spo11 but undergo complete meiotic
Alternatively, meiotic infidelity may simply be sexual cycles (discussed further below).
tolerated in scenarios wherein a sufficient num- We regard meiosis as accomplishing four
ber of viable, fit progeny are generated and/or functions: (1) reducing ploidy ( parasexuality
the consequences of aneuploidy are small also accomplishes this, albeit less efficiently);
enough to be tolerated by the population. (2) purging deleterious alleles (Kondrashov
1988) and unmasking advantageous recessives
when meiotic products are haploid ( parasexu-
MEIOSIS
ality also does this); (3) reducing ploidy while
An alternative view is that meiosis arose early, also generating complete chromosome sets rath-
without prior parasexual experimentation, as a er than incomplete or chaotic sets (the elegance
means to generate haploid progeny from a dip- of meiosis I); and (4) generating recombinant
loid progenitor. Early meiosis was likely messy offspring via independent assortment and
and inaccurate—perhaps only somewhat better crossing over in heterozygotes. We focus here
than parasexual changes in ploidy—with more on meiosis, and later consider mating type and
accurate mechanisms evolving subsequently. its imposition of heterozygosity on the system.
Like parasexuality, meiosis also serves as a mech- Meiosis entails chromosome segregation,
anism to purge deleterious mutations from the and thus it is important to consider the nature

of the chromosomes involved given that most sis and the persistence of sister-chromatid co-
modern prokaryotes have circular genomes. hesion through meiosis I into meiosis II.
There are several reasons to suggest that proto- There are at least two models for the promo-
eukaryotes had linear chromosomes, or at least tion of recombination between homologs ver-
that these arose when meiosis evolved. The ear- sus sister chromatids. In model A, 2N ! 4N
liest protoeukaryotes may have had only one or DNA replication (hereafter meiotic replication)
a few linear chromosomes encompassing the does not occur. Therefore, pairing can only oc-
entire genome (which also necessitated the evo- cur between homologs (because replication is
lution of centromeres and telomeres to allow required to produce sister chromatids), and
faithful segregation and protect the ends from breaks stimulate a crossover between them, gen-
decay). Linear chromosomes are required be- erate tension, and promote segregation (note
cause crossing over between two circular chro- that breaks might also stimulate their pairing).
mosomes generates a circular dicentric that is This is similar to repair of DNA DSBs that oc-
unstable (the chromosome is broken if the two curs in diploid fungal and human cells in the G1
centromeres attach to opposite spindle micro- phase of the cell cycle before DNA replication
tubules). Even crossing over between one linear (Takata et al. 1998).
and one circular chromosome will yield a linear In model B, if we allow meiotic replication
dicentric that would also be unstable. The ad- of the 2N to 4N state, there are now both chro-
vent of sexual crosses may well have driven the mosome homologs and sister chromatids. Even
advent of the linear chromosome: An ancestral without chromosome alignment and synapsis,
protoeukaryote might have had two circular DNA DSBs can still be repaired via either the
chromosomes with centromeres; their recombi- homolog chromatid or the sister chromatid. If
nation would have yielded a circular dicentric this occurs with the homolog, tension will be
that, when subjected to incomplete breakage- generated on the meiotic spindle, whereas if
fusion-reunion cycles, could have given rise to recombination occurs with the sister chromatid,
linear chromosomes. Alternatively, linear chro- tension will not be generated (tension is gener-
mosomes may have arisen in other ways, as has ated when the centromeres of the homologs at-
occurred in some bacteria and some organelle tach to microtubules from different spindle pole
genomes, and predated sexual crosses. bodies/centrosomes; when this does not occur,
The evolution of meiosis resulted in homo- segregation is aborted [Nicklas 1997]). So even
log chromosome pairing, independent assort- if there were, for example, 10 breaks per chro-
ment, chiasmata-based crossing over, and ploi- mosome, and there were a 10:1 preference for
dy changes (2N to 4N to 2N to 1N). Independent repair with the sister chromatid versus the ho-
assortment produces diversity in the meiotic molog chromatid, that single crossover per
products of heterozygotes regardless of levels chromosome would achieve the required ten-
of crossing over, and chiasmata have been shown sion.
to play an additional role, aligning homologous Either starting point could evolve into a
chromosomes and providing tension on the more efficient system that reduces recombina-
spindle for accurate meiosis I segregation (Hi- tion with the sister chromatid and/or promotes
rose et al. 2011). recombination with the homolog. Why then
At a molecular genetic level, the evolution of even include the meiotic replication step? Be-
meiosis would have entailed the following inno- cause the key events in a modern meiosis I, in-
vations: (1) mechanisms to promote breaks that cluding breaks and repair, occur in a 4N context,
stimulate meiotic recombination frequencies to it is difficult to speculate about original condi-
higher levels than mitotic recombination fre- tions, but one certain outcome is that more mei-
quencies; (2) crossovers that occur between ho- otic progeny are produced (four instead of two),
mologs and not between sister chromatids; (3) and in many biological settings brood size mat-
DNA replication stimulated at meiosis I and ters. The chances are also increased that there
inhibited at meiosis II; and (4) homolog synap- will be at least one viable spore product given

that meiosis was doubtless less accurate ab initio mosome arms is released but cohesion near the
than it later evolved to be. kinetochores persists to allow homologs to seg-
Perhaps the most interesting hypothesis for regate. Each of these steps is mediated by mei-
why replication occurs before meiotic recombi- osis-specific elements that evolved from ances-
nation in meiosis I is that in the pre-Spo11 era, tral roles: step 1 by Spo11 (a former archael
the sister-chromatid copies served as the source topoisomerase); step 2 by Rec8 (S. pombe and
of DSBs. DSBs are formed by replication of other organisms) or the monopolin complex
nicked DNA, in which the nicks might have (S. cerevisiae) and temporal orchestration of
been incurred by UV or gamma rays before microtubule-kinetochore interactions to pro-
Spo11, and DSBs (but not nicks) are potent mote monopolar rather than bipolar spindle
stimulators of homologous recombination. attachment (Miller et al. 2012); and step 3 by
Such a model is supported by the finding that Rec8 again (and other related cohesins in many
the meiotic defects of S. cerevisiae spo11 mutants organisms) as the meiosis-specific cohesins that
can be in part suppressed by gamma irradiation, replace mitotic cohesins (Parisi et al. 1999) and
suggesting that random DSBs can suffice to en- persist at kinetochores through meiosis I. Rec8
hance meiotic crossovers and increase spore vi- and related meiotic cohesins can also serve ad-
ability and germination (Thorne and Byers ditional roles, including the enhancement of
1993; Celerin et al. 2000). Notably, other types synapsis and recruitment of recombination fac-
of DNA lesions, such as abasic sites or nicks tors (Wilkins and Holliday 2009).
generated by DNA deaminase acting to convert That Spo11 and its associated cofactors are
cytosine to uracil (a substrate for uracil N-gly- nearly universal throughout eukaryotes sug-
cosylase), can restore meiotic recombination in gests that it was already a key element in the
mutants of the fission yeast Schizosaccharomyces meiosis of the LECA. The one known exception
pombe lacking Spo11 (rec12) without generating is the slime mold D. discoideum and closely re-
DSBs (Pauklin et al. 2009). These studies show lated species, which appear to have complete
that one can take the activation-induced deam- sexual cycles including meiosis but which lack
inase (AID) enzyme that stimulates somatic hy- Spo11 (Eichinger et al. 2005; Sucgang et al.
permutation of antibody-encoding genes in im- 2011). This implies that the slime molds are a
mune cells, express it heterologously in fission derived rather than ancestral state, but that said,
yeast mutants lacking Spo11, and the resultant it seems likely that other types of DNA damag-
DNA lesions and their processing promote mei- ing pathways have taken the place of Spo11 in
otic recombination, restore fidelity of chromo- slime molds. These novel pathways remain to be
some segregation, and enhance spore viability identified, and may also function in aspects of
and germination frequency. meiosis in other extant organisms. Elucidating
A key innovation—indeed, the hallmark of how Spo11-independent meiotic recombina-
meiosis—was synapsis between homologs. For tion can occur should shed further light on pos-
this to succeed, mechanisms promoting sister sible early steps in the evolution in meiosis in a
chromatid cohesion were required. The unique pre-Spo11 era that presumably existed in the
feature of meiosis compared with mitosis is posited transition from parasexual to sexual ex-
meiosis I in which chromosome homologs rath- perimentation in the extinct protoeukaryote
er than sister chromatids segregate in a reduc- lineages that antedate the LECA.
tional division (Watanabe 2004; Wood et al. It is worth noting explicitly that original
2010). For this to occur, there are three key steps: versions of meiosis may have taken tetraploids
(1) homologs must synapse, and this is typically to diploids rather than diploids to haploids, or
driven by Spo11-dependent DSBs that provoke octoploids to tetraploids for that matter be-
meiotic recombination; (2) the kinetochores cause the key metric is ploidy transition rather
from sister chromatids both attach to microtu- than absolute ploidy level; there is no basis to
bules from the same spindle pole body via mo- the claim that the original meiotic products
nopolar attachment; and (3) cohesion of chro- were haploid, other than the parsimony argu-

ment that because they are so now then they loid cell adherence to trigger intracellular signals
may also have been so when they originated. that elicited the conditions for cell – cell fusion.
That said, haploid meiotic products have the Modern sexual recognition systems are over-
advantage of allowing the “purging” of delete- whelmingly prezygotic—cells recognize “self ”
rious alleles and the “unmasking” of potentially via pheromones or cell-surface molecules that
adaptive recessive alleles, both clear benefits of stimulate zygotic cell fusion—but postzygotic
the modern version of meiosis. mechanisms have also evolved that permit cells
to monitor how similar their chromosomal se-
quences are with respect to their fusion partner.
REGULATION OF CELL– CELL FUSION For example, when different yeast species are
induced to fuse with each other, their hybrid is
Restricting Cell – Cell Fusion to “Self”
unable to proceed smoothly through meiosis,
Interactions
even if all the chromosomes are colinear and
Although the initial pressure to develop meiosis syntenic, because a higher level of DNA mis-
may have been to effect ploidy reduction, the matches provokes the mismatch repair machin-
process evolved into something far more so- ery to abort meiotic recombination events, and
phisticated: a mechanism to generate complete spores fail to germinate (Chambers et al. 1996;
chromosome sets during meiosis I and then Hunter et al. 1996). That said, there are examples
halve their ploidy during meiosis II. In order in which hybrids that have formed from cross-
for haploid products to recapitulate these species cell – cell fusions have ultimately given
events, and hence again avail themselves of the rise to new species, such as the posited origin
advantages of diploidy, they must in turn fuse of S. cerevisiae from an ancestral whole genome
together to create diploids that are both capable duplication event following fusion of two relat-
of meiosis and precluded from undergoing ad- ed, but different, yeast species (Wolfe and
ditional fusion events. Indiscriminate cell–cell Shields 1997; Scannell et al. 2006). Exciting re-
fusions, although they may have generated im- cent studies report adaptive changes that occur
portant novelties during early protoeukaryotic in the genomes of such cross-species hybrid
evolution, generate disparate chromosome yeasts isolated and passaged under laboratory
complements that are toxic to a successful mei- conditions; genome rearrangements arise re-
osis. Hence the invention of meiosis puts pres- peatedly and independently (Dunn et al. 2013).
sure on the development of mechanisms where-
in haploid cells first recognize other haploid
Limiting Expression of Recognition/Fusion
cells with the same chromosome complement,
Molecules to Particular Conditions
and then fuse with them selectively.
Recognition of self is not, of course, a eu- In haploid eukaryotic microorganisms, the dis-
karyotic novelty. The widespread occurrence of play of self-recognition/fusion molecules is
biofilm formation and quorum sensing in mod- usually not constitutive. Instead, postmeiotic
ern bacteria (Vlamakis et al. 2013) and archaea cells first enter a mitotic phase and multiply
(Koerdt et al. 2010; Frols 2013) suggests that the until receiving an exogenous signal. In yeasts
forebears of protoeukaryotes likely engaged in and Volvox, a pheromone is detected; in most
such self-recognition behaviors as well. Modern other microbes some kind of environmental
prokaryotic systems feature the secretion of lin- stress, such as the depletion of essential nutri-
eage-specific extracellular matrix materials and ents in the environment (often nitrogen), is de-
small molecules; their receptor-mediated per- tected (Sager and Granick 1954; Ueno et al.
ception then triggers signal-transduction cas- 2001). Detection of such signals then induces
cades that modulate growth and metabolism. the expression of genes encoding the necessary
Hence self-recognition modules presumably ex- components for adhesion and fusion, where
isted in the protoeukaryotic gene pool that, with cells displaying such competence are called
evolutionary tinkering, allowed like-like hap- gametes. Again, such a system need not be con-

sidered a eukaryotic novelty because prokary- tions might have been heterotypic, like pres-
otes also limit production of their biofilm and ent-day integrins that adhere to intercellular
quorum-sensing components to particular en- adhesion molecules (ICAMs) (Kim et al. 2011).
vironmental circumstances (Ng and Bassler Any heterotypic recognition/adhesion pairs
2009). (hereafter H1/H2) in a protoeukaryote would
Pheromone-induced control over mating be candidates for the next posited stage in the
competence has the advantage of requiring origins of sex, namely, the exclusive expression
that a potential mating partner is nearby. A of H1 in gametes that we will generically call
stress-imposed elicitation of mating compe- plus mating type and exclusive expression of
tence has the effect of enabling the mitotic prog- H2 in gametes that we will call minus mating
eny of meiotic products to first test out their type. The regulatory system that limits expres-
haploid genomes in the environment into sion of mating-related genes to one or the other
which they germinate, with deleterious alleles type of gamete will be called the mating-type-
purged and adaptive alleles/genomes spreading determination (MTD) system, with that leading
into the population. The survivors can then to plus mating type called MTDP and the other
avail themselves of the benefits of entering the leading to minus mating type called MTDM.
diploid state when the environment is no longer A simple model for the incarnation of mat-
supportive. Life cycles with extended haploid ing type might go as follows. (1) The original
phases and occasional diploid phases are often MTD was a transcription factor that, in re-
said to engage in facultative sex, as contrasted sponse to the appropriate exogenous signal, ac-
with the obligate sex that characterizes most tivated expression of unlinked genes encoding
land plants and animals. The conditions that H1 and H2 by binding to common upstream
elicit facultative sex may be difficult to identify, sites. (2) A copy of the MTD gene mutated such
meaning that sexual interactions may occur in that the DNA-binding motif of its protein prod-
the wild that investigators have thus far failed to uct was altered, converting it to MTDP . (3) Mu-
recapitulate in the laboratory (Fritz-Laylin et al. tations altered the upstream sequence of the
2010; Grimsley et al. 2010; Halary et al. 2011; gene encoding H1 to match this new MTDP
Lahr et al. 2011). configuration so that MTDP now induced
Systems that detect an appropriate exoge- only H1 expression. (4) The original version
nous signal—hormonal and/or environmen- of MTD continued to activate expression of
tal—and elicit downstream gametic differenti- H2; because it is now different from MTDP , it
ation are expected to include receptor is designated MTDM.
components that are coupled to the regulation The outcome would then be that, with en-
of gene expression via signal-transduction cas- vironmental stress, plus gametes displaying H1
cades. Such pathways are well understood in the will only adhere and fuse with minus gametes
fungal response to pheromones (Di Segni et al. expressing H2. Because the MTDP and MTDM
2011; Kim et al. 2012), but they have thus far alleles now elicit the formation of two different
remained more elusive in microbes that respond kinds of gametes, we can say that they specify
to environmental cues because the expression of mating type and that their chromosomal locus
many non-sex-related genes is also influenced defines the mating-type (MT) locus, such that
by environmental stress. we speak of the MT-plus and MT-minus loci.
And because the MT loci are allelic, indepen-
dent assortment would generate two plus and
THE ORIGINS OF MATING TYPE
two minus haploid products at each meiosis.
The original self-recognition molecules in pro- That there would be selection for and even-
toeukaryotic gametes might have engaged in tual fixation of such a heterozygous system is
homotypic interactions, like present-day cad- inherent in the argument most often offered
herins that adhere to one another (Hulpiau as the “reason” for eukaryotic sex: its promotion
and van Roy 2009). Alternatively, the interac- of outcrossing and hence the generation of nov-

el genotypes via independent assortment and/ absent from the MT-plus locus. Any organism
or crossing over. Although meiosis operates cor- expressing an endogenous or transgenic MID
rectly when the chromosomes are fully isogenic, gene differentiates as a minus gamete, switching
imposing the requirement that the fusing gam- on minus-specific genes and not expressing
etes be heterozygous, at least at the MT-plus/ plus-specific genes, whether or not the MT-
MT-minus locus, introduces a whole new role plus locus is also present. When MID is absent
for meiosis in the sexual life cycle. or mutant, organisms differentiate as plus (Fer-
Outcrossing can carry a proximal cost as ris and Goodenough 1997; Lin and Goode-
well, namely, the disruption of adaptive geno- nough 2007). Interestingly, an analogous system
types during independent assortment and also operates in mammals. The Y chromosome
crossing over (Maynard Smith 1976; Otto and SRY gene, encoding a Sox transcription factor,
Gerstein 2006; Goodenough et al. 2007; Escobar dictates male differentiation when present; fe-
et al. 2008), a cost that can be overridden by a male differentiation occurs in its absence (Se-
shift to asexuality/homothallism/inbreeding kido and Lovell-Badge 2009).
or by the occurrence of speciation. Clearly, how- The S. cerevisiae version is similar except
ever, this cost has not overridden the benefits of that two tightly linked genes in the MATa locus,
genetic shuffling within a population to gener- a1 and a2, collectively perform the same func-
ate phenotypes adapted to an ever-changing en- tion as MID: The a1 product (an a-domain
vironment, as attested by the retention of the transcription factor) induces a-specific genes
meiotic option in most if not all major eukary- and the a2 product (a homeobox transcription
otic lineages for more than a billion years. factor) represses a-specific genes (Ni et al.
A number of theoretical studies, cited in 2011). The MATa locus lacks the a1 and a2
Hadjivasiliou et al. (2013), have posited that genes; cells inheriting MATa, or cells carrying a
the uniparental inheritance of organelles, con- deletion of MAT, differentiate as a gametes.
sidered in a later section of this review, preced- Modern microbial gamete-differentiation
ed, and led to, the instantiation of mating types. programs have expanded well beyond our min-
Hadjivasiliou et al. (2013) present arguments imalist model—many plus/a-specific genes are
against this hypothesis, concluding that mat- induced in addition to the H1 equivalent, and
ing-type systems would have been buttressed many minus/a-specific genes are induced in
but are not likely to have been initiated by uni- addition to the H2 equivalent (Mata et al.
parental systems. 2007; Snell and Goodenough 2008; van Werven
et al. 2012)—but the core principle holds. The
frequent turnover and convergent evolution of
MODERN VERSIONS OF MTD SYSTEMS
MT systems indicates the importance and im-
AND MT LOCI
pact of variations in this system.
Two MTD systems are well characterized in The MT loci of yeasts contain only two con-
modern eukaryotic microbes, and both prove tiguous transcription-factor genes; the genes en-
to use a variation on our simple model. Instead coding sexual traits are found elsewhere in the
of there being two MTD alleles, there exists a genome and regulated in trans. In several other
single determinant which, when expressed, dic- organisms, MT loci are more complex (Ferris
tates the differentiation of one mating type. et al. 2002, 2010; Metin et al. 2010; Umen
When this determinant is absent, the second 2011; De Hoff et al. 2013): As in the yeasts,
mating type differentiates “by default.” most genes encoding sexual traits are not linked
In the Chlamydomonas reinhardtii version to MT and are regulated in trans, but some sex-
of this arrangement (Goodenough et al. 2007), related genes have come to reside in MT along
the MID gene encodes a transcription factor in with the mating-type determinant(s). These
the RWP-RK family (Lin and Goodenough genes are typically interspersed with non-sex-
2007; Konishi and Yanagisawa 2013). The MT- related genes, and their linkage to MTDs is es-
minus locus carries a copy of MID, whereas it is tablished via some form of recombinational re-

pression. Extreme examples of this phenome- in these cases more encounters are sexually fer-
non are the dimorphic (e.g., XY and WZ) sex tile (.98% in some basidiomycetes). But more
chromosomes of mammals, birds, and some outcrossing is not always better, and in basidio-
land plants, in which recombination is repressed mycete fungi there are multiple independent
by reducing the DNA homology needed for syn- transitions from the tetrapolar outcrossing spe-
apsis to short pseudoautosomal regions (Waters cies with thousands of sexes back to bipolar
et al. 2007; Ellegren 2011). In the fungus Cryp- species with just two mating types, where it
tococcus neoformans and the green algae has been suggested that different environments
C. reinhardtii and V. carteri, numerous chromo- favor outcrossing versus inbreeding sexual cy-
somal rearrangements act to inhibit successful cles (Heitman et al. 2013).
synapsis, assuring, for example, cotransmission Yet another way to enhance the efficiency of
of the MID gene and the gene encoding the mi- finding a compatible mate is to dispense entirely
nus recognition protein in C. reinhardtii (Ferris with the requirement of different mating types
et al. 2002, 2004, 2010). Although this feature of for cell – cell fusion. In such unisexual species,
complex MT loci and sex chromosomes assures any isolate can fuse with any other (under some
that certain sex-related genes are cotransmitted, conditions in the presence of a third partner
the fact remains that most sex-related genes are that serves as a pheromone donor to trigger
dispersed throughout the genome. Hence the like-with-like cell fusion in ménage à trois mat-
“purpose” of and the pressures generating such ings). This strategy has been adopted by two of
genomic differentiations are not yet clear. the most common systemic human fungal path-
In modern multicellular organisms, the ogens, C. neoformans and C. albicans, and also
MTD systems are themselves complex (Pomian- several nonfungal eukaryotic microbial patho-
kowski et al. 2004; Kimchi et al. 2007; Salz gens (Lin et al. 2005; Heitman 2006, 2010; Pox-
2011), highly diverse (Haag and Doty 2005), leitner et al. 2008; Alby et al. 2009; Wendte et al.
and often labile (Charlesworth and Mank 2010; Carpenter et al. 2012).
2010), and the H1/H2 programs they specify Finally, many lineages, including algae and
have expanded to include control over tissue fungi, abandon heterothallism for homothal-
and organ differentiation and, in animals, brain lism, wherein a single haploid genome contains
and behavioral patterning. both MTDP and MTDM equivalents; these are
tightly linked in the case of some filamentous
ascomycetes, and unlinked in others (Vanwin-
Multiple Mating Types and Homothallism
kle-Swift and Burrascano 1983; Lee et al. 2010;
In addition to the cost of outcrossing noted Ni et al. 2011). One or the other determinant is
earlier, the introduction of heterozygous mating expressed in individual gametes during the
types restricts fusion partners to half the popu- course of gametogenesis, the result being “self-
lation. In most modern eukaryotes, this handi- fertilization.” Heterothallic species often have
cap has been assuaged by the evolution of closely related homothallic counterparts (Ny-
countless systems for identifying the opposite gren et al. 2011), indicating that this trait is sus-
type via pheromones and mating behaviors, en- ceptible to evolutionary pressures. Modern
hancing the efficiency of finding a mate, but multicellular parthenogens are also known to
options are still limited to half the population. engage in “occasional sex” (Pires-daSilva 2007;
In some lineages, the odds have been improved D’Souza and Michiels 2010).
by the presence of multiple mating types—three
or more in Dictyostelium (Bloomfield et al.
MATING-TYPE-REGULATED COUPLING
2010, 2011), seven in Tetrahymena (Phadke
OF DIPLOIDY TO THE FORMATION
et al. 2012; Cervantes et al. 2013; Umen 2013),
OF RESTING SPORES
13 in Physarum polycephalum (Collins and Tang
1977; Clark and Haskins 2010), and often thou- In previous sections we have suggested that the
sands in the basidiomycetes (Raper 1966)—and selective advantage of diploidy lies in the pres-

ence of at least two copies of each gene, allowing as S. pombe that arrest in the G2 phase of the
complementation of recessive lethal mutations cell cycle to enable repair from the other sister
and the potential generation of novel alleles/ chromatid.
genes in the second copy. At some point during In those cases in which the molecular basis
the evolution of protoeukaryotes, there evolved for shifting to diploid resting-spore differentia-
an additional and far more immediate and tan- tion is understood in eukaryotic microbes, the
gible benefit to transitions from the haploid to transition is triggered by the formation of a het-
the diploid state, namely, restricting the forma- erodimeric transcription-factor complex, with
tion of a resting spore to diploid cells, diploid subunits that we will generically designate P
cells, a capability that came to be controlled by and M (for plus and minus). Synthesis of P is
mating type. restricted to plus gametes and hence regulated by
Haploid resting spores are produced by sev- MTDP; synthesis of M is restricted to minus
eral modern bacterial lineages (Henriques and gametes and hence regulated by MTDM. Fusion
Moran 2007); they are also found in several of plus and minus gametes permits the forma-
amoeba lineages (West 2003; Chatterjee et al. tion of P/M heterodimers, and these are
2009; Fritz-Laylin et al. 2010) and in many fungi uniquely capable of activating expression of dip-
(Feofilova et al. 2012) and algae (Hagen et al. loid-specific genes (and repressing haploid-spe-
2002). Hence it is plausible to propose that the cific genes), including genes involved in resting-
protoeukaryote possessed a genetic program for spore formation and, at some later stage, genes
haploid spore differentiation that was indepen- involved in entering meiosis and spore germi-
dent of any sexual process. Sporulation pro- nation. Importantly, it is not necessary to posit
grams typically entail the assembly of a novel that the P/M factor orchestrates all spore- and
cell wall that preserves viability in the face of meiosis-related genes directly—these programs
noxious environmental circumstances such as are presumably coordinated by preexisting cir-
high temperature, freezing, desiccation, preda- cuits from haploid sporulation and diploid mei-
tion (Coluccio et al. 2008), and exposure to otic programs. Rather, P/M is posited to initiate
ionizing radiation. They also impose modula- a cascade that permits the regulated expression
tion of gene expression to a minimalist “main- of these genes during diploid-spore maturation
tenance” mode and the accumulation of poly- and subsequent germination.
saccharide and lipid storage products for use There is, of course, a pleasing symmetry in
during germination and the resumption of mi- this arrangement in that the P/M requirement
tosis when conditions improve. Hence the pro- for diploid differentiation mirrors the H1/H2
grams that govern haploid spore formation are requirement in the fertilization process, both
expected to include “spore-specific” genes that being regulated by mating type. In a recent
are not expressed in cycling cells and are acti- review, Perrin (2012) lifts up this feature as
vated at the time that the circumstances dictate well, noting that “mating types have evolved to
the importance of shifting to a resting state. switch on the right program at the right mo-
As noted earlier, such deteriorating con- ment.”
ditions commonly also trigger the expression The P/M pairs thus far identified in mi-
of the MTD systems that control gametic recog- crobes are usually members of the homeopro-
nition/fusion programs. Therefore, the stage tein transcription-factor family: a1/a2 in
would be set for mating type to acquire control S. cerevisiae (Madhani 2007) (in which a2 per-
over diploid resting-spore formation as well, forms “double duty,” functioning as well in the
the spore thereby endowed with both long- haploid phase); Sxi1a/Sxi2a in C. neoformans
term viability and the advantages, already listed, (Hull et al. 2002, 2005); bW/bE in Ustilago
of generating recombinant progeny via an even- maydis (Schulz et al. 1990); and GSP1/GSM1
tual meiosis. An advantage of diploid spores in C. reinhardtii (Lee et al. 2008a). The one
could also be to promote repair of DSBs dur- known exception is that HMG-family or a-
ing dormancy, similar to haploid yeasts such box transcription factors drive differentiation

in the zygotes of filamentous ascomycetes and function in photosynthesis, and presequences

zygomycetes (Glass et al. 1988; Fraser et al. 2007; that target their import into the cyanelle have
Idnurm et al. 2008; Lee et al. 2008b), groups that been identified. Hence the posited gene-transfer
lack MT-encoded/regulated homeoproteins. events that accompanied mitochondrial and
Whether these factors dimerize or act indepen- chloroplast domestication are apparently being
dently on common target promoters is not yet recapitulated in Paulinella.
known. Yeast two-hybrid studies failed to detect Importantly, what is already in place in Pau-
dimerization between the SexM and SexP pro- linella is a mechanism to coordinate the repli-
teins of Phycomyces (A Idnurm, unpubl.), sug- cation of the cyanelle’s DNAwith the replication
gesting that novel mechanisms may operate. of the amoeba’s DNA such that, at each mitosis,
An explosive expansion of homeoprotein- each daughter cell inherits two cyanelles. Be-
encoding genes has accompanied the evolution cause the growth rate of free-living Synechococ-
of multicellularity in animals and land plants, cus (6– 12 h doubling time) far exceeds the
with homeoprotein-based combinatorial con- growth rate of testate amoebas (1– 3 d dou-
trol exerted over core domains of the body bling time), the imposition of such control is
plan: PBC/MEIS þ HOX proteins specify the presumably an early and critical event in estab-
anterior– posterior axis of animals (Mann and lishing any endosymbiotic relationship, pre-
Morata 2000), and KNOX þ BELL proteins venting the engulfed bacterium from over-
specify the initiation of the moss sporophyte whelming the host cell, and it was presumably
program (Sakakibara et al. 2013) and regulate quickly established during the protoeukaryote’s
the architecture of shoot apical meristems acquisition of protomitochondria and proto-
(Hake et al. 2004). As expanded elsewhere (Lee chloroplasts. Eukaryotes vary widely in num-
et al. 2008a), it is appealing to posit that the bers of mitochondria and chloroplasts per cell
combinatorial-control “idea,” originally gov- and in numbers of genomes per organelle, but
erning the differentiation of diploid zygotic in a given microorganism, or cell type in a mul-
spores, was co-opted to govern the differentia- ticellular organism, these values are maintained
tion of multicellular diploids. at constant levels.
The development of a sexual cycle would be
expected to place such a control system in jeop-
MATING-TYPE-REGULATED ardy. The fusion of gametes would generate dip-
TRANSMISSION OF ORGANELLE GENOMES loid zygotes with twice the organelle- genome
tally, and without some way to return to the
Theoretical Considerations
“organelle-haploid” value, meiotic products
The stages in the domestication of a proteo- would be “organelle-diploid” and then, in the
bacterium into a mitochondrion, a seminal next round, “organelle-tetraploid” and so on.
achievement of the protoeukaryote, are not This dilemma suggests a hypothesis regard-
known. However, the analysis of an ongoing ing the origin of the near-universal pattern of
domestication process—the conversion of a organelle inheritance in modern sexual eukary-
Synechococcus cyanobacterium into a “cyanelle” otes—the uniparental (UP) transmission of or-
( protochloroplast) in the testate amoeba Pauli- ganelle genomes to meiotic products. In this
nella chromatophora (Rhizaria)—is providing scenario, the solution adopted by the LECA
fascinating insights into what is entailed (Chan was to (1) tag the organelles residing in plus
et al. 2011; Bodyl et al. 2012; Nowack and Gross- gametes differently from the organelles residing
man 2012). During the 60 million years since the in minus gametes, and (2) devise a system that
estimated onset of this conversion, the genome recognizes these tags in the diploid zygote and
of the endosymbiont has undergone an estimat- selectively prevents one set of organelles/organ-
ed 75% reduction in size, and roughly 1% of the elle genomes from being transmitted, thereby
amoeba’s nuclear genes are of endosymbiont or- reestablishing the “organelle-haploid” number
igin. Many of these genes encode proteins that in all four meiotic products. By placing the tag-

ging system under the purview of the mating- the two genomes might assemble into defective
type system, the LECA would have been able complexes.
to control organelle ploidy using the same The zygotes of budding and fission yeasts
system that it used to regulate nuclear ploidy, receive mitochondrial genomes from both par-
albeit the downstream mechanisms are totally ents and do not destroy one set (Solieri 2010);
different. however, they carefully segregate mitochondria
That modern UP systems are sensitive to during the early diploid mitotic divisions such
organelle ploidy has been shown in C. reinhard- that daughter-cell clones become “homoplas-
tii. The usual pattern, described in detail below, mic” for one or the other input genome (Basse
is that chloroplast genomes from the minus par- 2010). Similarly, C. reinhardtii meiotic products
ent are destroyed by nucleases in the early zy- manipulated to be heteroplasmic for chloro-
gote, leading to UP inheritance of plus genomes. plast genomes rapidly “sort out” to yield homo-
However, if the zygotic input of plus chloroplast plasmic mitotic clones within 10 – 20 cell gen-
genomes is reduced, either by growth in FuDR erations (VanWinkle-Swift 1980; Forster et al.
(Wurtz et al. 1977; Matagne and Beckers 1983; 1980). Thus most modern eukaryotic organ-
Armbrust et al. 1995) or by the mat3 mutation isms manage to acquire homoplastic organelle
(Gillham et al. 1987; Armbrust et al. 1995; profiles by one means or another, suggesting
Umen and Goodenough 2001), destruction of that this condition is adaptive.
minus genomes is aborted and chloroplast DNA Countering this inference is the demonstra-
inheritance is biparental (BP). tion that in Medicago (clover) (Matsushima et al.
In most modern egg/sperm systems, the egg 2008), Passiflora (Hansen et al. 2007), and Myti-
can have millions of organelle genomes, where- lus (mussel) (Jha et al. 2008), organelle inheri-
as sperm are either stripped of organelles or tance is or can be biparental without known
their organelle DNA is destroyed by the zygote. adverse consequences. Clearly there are funda-
Therefore, if an “organelle ploidy” system mental features of UP that are not yet under-
played a role in establishing UP in isogamous stood, leading us to quote a quip from Maynard
organisms, this consideration is clearly irrele- Smith (1976) regarding another sex-related
vant to modern anisogamous organisms. enigma: “One is left with the feeling that some
A second consequence of UP inheritance is essential feature of the situation is being over-
that at each sexual generation, a uniform set of looked.”
organelle genomes is exposed to natural selec-
tion in the “unmasked” haploid state, and a
Modern UP Systems
uniform set of organelle genomes is eliminated
from the gene pool altogether. This may serve to That UP inheritance of organelle genomes is
guard against “selfish” genomes (Hurst and controlled by mating type was first discovered
Werren 2001) that might otherwise infest and by Sager and Tsubo (1961) in the alga C. rein-
destroy the population, or even the species, with hardtii: Traits encoded by chloroplast genomes
unregulated organelles. Again we encounter and carried by plus gametes are usually transmit-
meiotic symmetry in that such “purging” func- ted to all meiotic progeny, whereas few if any of
tions are also a feature of meiosis. the progeny inherit traits encoded by chloroplast
A third consequence of a UP system is that it genomes and carried by minus gametes. Subse-
guards against “heteroplasmy,” the presence of quent studies showed that the reciprocal is true
two or more different organelle genomes in the for mitochondrial genomes: Those contributed
same organism. In a recent study, mice were ar- by minus gametes are transmitted, whereas those
tificially manipulated to be heteroplasmic for contributed by plus gametes are not (Aoyama
mitochondrial genomes, and they showed a et al. 2006). Both systems entail DNA degrada-
number of developmental and cognitive defects tion; shortly after gamete fusion, the minus-con-
(Sharpley et al. 2012); the investigators suggest tributed chloroplast chromosomes are de-
that disparate OXPHOS subunits encoded by stroyed by nucleases (Nishimura et al. 2002;

Kuroiwa 2010), whereas the plus-contributed crossed, progeny inherit mitochondria from ei-
mitochondrial chromosomes are destroyed ther parent and show a higher frequency of mi-
24 h later (Nakamura 2010). The GSP1/ tochondrial recombination (Fedler et al. 2009).
GSM1 heterodimer, described above, that trig- Correspondingly, when rga2 is expressed heter-
gers spore development, is also required to acti- ologously in a1 cells, the a1 mitochondrial ge-
vate these recognition/destruction programs; nome is now protected and again progeny in-
when disabled, inheritance of both chloroplast herit mitochondria from either parent. Finally,
and mitochondrial genomes is biparental (Nish- deletion of rga2 from a2 cells results in loss of
imura et al. 2012). Little is yet known about the the a2 mitochondrial genome and inheritance
molecular basis of the tagging systems except of mitochondria from the a1 parent—exactly
that the activity that serves to protect chloroplast the opposite of the pattern observed with
DNA from being destroyed is evidently encoded wild-type crosses. Thus rga2 protects the host
by gene(s) in the MT-plus locus (reviewed in cell mitochondrial genome, whereas lga2 func-
Goodenough et al. 1995, 2007). tions in mitochondrial destruction via a dyna-
In the basidiomycete C. neoformans, the mi- min-dependent mitophagy pathway (Mahlert
tochondrial genome is selectively inherited from et al. 2009; Nieto-Jacobo et al. 2012).
the parent of a mating type; a small proportion Although there is as yet no information on
of meiotic products inherit the a parent’s mito- the molecules that exert mating-type UP con-
chondrial genome or a recombinant mitochon- trol in most systems, the selective destruction
drial genome (Xu et al. 2000; Yan and Xu 2003; of one set of organelle genomes has been shown
Toffaletti et al. 2004). It is not known whether in several disparate radiations, including the
this process involves a selective destruction of the chlorophytes Gonium (Setohigashi et al. 2011)
parental a mitochondrial genome ( possibly via and Bryopsis (Kuroiwa and Hori 1986), the ul-
mitophagy), preferential migration of the a mat- vophyte Ulva (Kagami et al. 2008), brown algae
ing-type mitochondria into the zygote, or both (Motomura et al. 2010), the slime mold Physa-
(Gyawali and Lin 2011). What is known is that rum (Moriyama and Kawano 2010), Drosophila
both the SXI1a and the SXI2a homeodomain (DeLuca and O’Farrell 2012), the fish Orizias
proteins that activate the a/a zygotic program (Nishimura et al. 2006), and the mouse (Ka-
are required for UP mitochondrial inheritance neda et al. 1995; Kuroiwa 2010; Sato and Sato
(Yan et al. 2004; Yan et al. 2007), just as in the 2013). Notably, in the vertebrate examples, the
C. reinhardtii system. Recent studies also provide sperm organelles enter the egg but are quickly
evidence for both prezygotic and postzygotic and selectively eliminated in the zygote in a spe-
levels of control, with the Mat2 pheromone-re- cies-specific fashion (Kaneda et al. 1995). In
sponse high-mobility group (HMG) factor play- land plants, plastids are excluded from the
ing a role in prezygotic marking of mitochon- sperm cell or are left behind in synergid cells
drial genomes (Gyawali and Lin 2013), again during fertilization (Mogensen 1996; Liu et al
similar to the system in C. reinhardtii. 2004); mechanisms are again unknown.
In the plant pathogenic basidiomycete U.
maydis, sexual reproduction results in UP mi-
SEX AND SPECIATION
tochondrial inheritance that is also controlled
by the mating-type locus. The mating-type lo- A signature feature of eukaryotes is that they
cus, encoding the pheromones and pheromone speciate, segregating into closely related popu-
receptors necessary for mate recognition, oc- lations that fail to respond to each other’s mat-
curs as two alleles. One (a1) encodes just the ing cues to form zygotes ( prezygotic isolation)
pheromone and pheromone receptor genes; and/or form zygotes that fail to produce a viable
the other (a2) encodes both of these and also next generation ( postzygotic isolation). Postzy-
two additional genes (lga2 and rga2) that govern gotic incompatability between nuclear and mi-
UP mitochondrial inheritance during sexual re- tochondrial genomes (Chou and Leu 2010) or
production. When a2 mutants lacking lga2 are between multiple nuclear loci (Kao et al. 2010)

have both been shown to play a role in Saccha- the inclusion of premeiotic DNA replication as a
romyces species incompatibilities. Hence sex-re- first step of meiosis might have been to replicate
lated genes are integral to establishing species across nicks and provide DNA double-strand
boundaries. As developed more fully elsewhere breaks to promote meiotic recombination in
(Goodenough et al. 2007), it can be argued that the pre-Spo11 era. We also warmly acknowledge
“speciose” lineages, poised to branch into pop- the experimental and intellectual contributions
ulations with separate and distinctive gene of past and present members of our laboratories.
pools, are more likely to navigate long-term en- Research on sexual differentiation in the Good-
vironmental fluctuations and hence move enough laboratory has been supported by grants
through time (i.e., avoid extinction) than “non- from the National Science Foundation and the
speciose” lineages confined to more narrow National Institutes of Health, and in the Heit-
niche dimensions. man laboratory by NIH/NIAID R01 grant
A corollary of this argument is that speciose AI50113-10 and R37 award AI39115-16.
lineages are predicted to have “evolvable” pre-
zygotic mating systems, capable of generating
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Ursula Goodenough and Joseph Heitman
Cold Spring Harb Perspect Biol 2014; doi: 10.1101/cshperspect.a016154
Subject Collection The Origin and Evolution of Eukaryotes
The Persistent Contributions of RNA to Eukaryotic Origins: How and When Was the
Eukaryotic Gen(om)e Architecture and Cellular Mitochondrion Acquired?
Function Anthony M. Poole and Simonetta Gribaldo
Jürgen Brosius
Green Algae and the Origins of Multicellularity in Bacterial Influences on Animal Origins
the Plant Kingdom Rosanna A. Alegado and Nicole King
James G. Umen
The Archaeal Legacy of Eukaryotes: A Missing Pieces of an Ancient Puzzle: Evolution of
Phylogenomic Perspective the Eukaryotic Membrane-Trafficking System
Lionel Guy, Jimmy H. Saw and Thijs J.G. Ettema Alexander Schlacht, Emily K. Herman, Mary J.
Klute, et al.
Origin and Evolution of the Self-Organizing The Neomuran Revolution and Phagotrophic
Cytoskeleton in the Network of Eukaryotic Origin of Eukaryotes and Cilia in the Light of
Organelles Intracellular Coevolution and a Revised Tree of
Gáspár Jékely Life
Thomas Cavalier-Smith
On the Age of Eukaryotes: Evaluating Evidence Protein Targeting and Transport as a Necessary
from Fossils and Molecular Clocks Consequence of Increased Cellular Complexity
Laura Eme, Susan C. Sharpe, Matthew W. Brown, Maik S. Sommer and Enrico Schleiff
et al.
Origin of Spliceosomal Introns and Alternative How Natural a Kind Is ''Eukaryote?''
Splicing W. Ford Doolittle
Manuel Irimia and Scott William Roy
Protein and DNA Modifications: Evolutionary What Was the Real Contribution of
Imprints of Bacterial Biochemical Diversification Endosymbionts to the Eukaryotic Nucleus?
and Geochemistry on the Provenance of Insights from Photosynthetic Eukaryotes
Eukaryotic Epigenetics David Moreira and Philippe Deschamps
L. Aravind, A. Maxwell Burroughs, Dapeng Zhang,
et al.
The Eukaryotic Tree of Life from a Global Bioenergetic Constraints on the Evolution of
Phylogenomic Perspective Complex Life
Fabien Burki Nick Lane
For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/
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